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At least 631 records · Page 35Linked to original sources
PubMed1997

Inhibition of corticosteroid-binding globulin caused by a severe stressor is apparently mediated by the adrenal but not by glucocorticoid receptors.

The effect of stress on serum corticosteroid-binding globulin (CBG) was studied in adult male Sprague-Dawley rats. CBG was measured either by a homologous radioimmunoassay (RIA) or by a binding assay (BA) using 3H-corticosterone. Exposure of adult male rats to a severe stressor such as immobilization (IMO) for 1 h did not alter serum CBG levels, but a significant decrease was found after 6 and especially 24 h IMO. This decrease was not observed after 24 h exposure to a milder treatment such as food and water deprivation. The effect of different periods of exposure to two stressors, IMO or restraint, was also studied. The following results were obtained:serum CBG levels were reduced by IMO, but only by restraint; IMO-induced reduction of CBG levels was always observed 24 h after starting exposure to IMO, independently of the actual period of exposure to the stressor; and IMO-induced inhibition of CBG was proportional to the hours of exposure to the stressor. Although IMO-induced inhibition of CBG was prevented by adrenalectomy, a role for glucocorticoid acting through their classical type II receptors is unclear as far as treatment of rats with the glucocorticoid receptor antagonist RU486 (100 mg/kg) did not prevent the inhibition caused by IMO. The present data clearly indicate that acute exposure to a stressor is able to decrease CBG levels provided that duration of exposure to the stressor and its intensity are high and that the effect is tested at least 6 h after the onset of stress. The effect appears to be mediated by some adrenal factor(s) other than glucocorticoids.

Adrenal Glands↗
PubMed1997

The effects of estradiol-17 beta infusion into fetal sheep in late gestation.

Activation of the hypothalamic-pituitary-adrenal (HPA) axis of fetal sheep during late gestation is associated with increases in plasma concentrations of adrenocorticotropic hormone (ACTH) and cortisol, and ultimately results in parturition. However, the mechanisms contributing to the concurrent increases in ACTH and cortisol are unclear. Plasma estradiol-17 beta (E2) concentrations increase progressively in the prepartum ovine fetus, and we hypothesized that E2 may influence HPA activity by affecting either basal and/or hypoxemia-stimulated ACTH release. We examined potential mechanisms, including altered expression of pro-opiomelanocortin (POMC) in fetal pituitary corticotrophs, and changes in corticosteroid binding globulin (CBG) and/or the enzymes 11 beta hydroxy steroid dehydrogenase (11 beta HSD)-1 or 11 beta HSD-2 in liver and placenta, that could alter negative feedback control. We infused fetal sheep at 127 d of gestation with either E2 (100 micrograms/24 h) or saline for 100 h. Fetal arterial blood samples were collected at 8 h intervals during the infusion of E2 or saline (n = 4), for measurement of basal plasma ACTH and cortisol concentrations, as well as plasma corticosteroid binding capacity (CBC). Placenta and fetal liver samples were collected at 100 h for measurement of placental 11 beta HSD-1 and 11 beta HSD-2 mRNA and hepatic CBG and 11 beta HSD-1 mRNA, by Northern blotting. Fetal pituitary samples were collected for measurement of POMC mRNA by in situ hybridization. In a separate experiment, fetuses were exposed to 2 h of hypoxemia at 75 h of E2 or saline infusion (n = 4), and fetal arterial blood samples were collected during the period of hypoxemia for measurement of plasma ACTH and cortisol concentrations. E2 infusion had no effect on basal plasma concentrations of ACTH or total cortisol, or on the stimulated levels of ACTH or total cortisol achieved in response to hypoxemia. Basal fetal pituitary POMC mRNA also did not change significantly with E2 infusion. No significant increases were observed in plasma CBC during E2 administration. However, hepatic CBG and 11 beta HSD-1 mRNA were significantly elevated in the livers of E2-treated fetuses. Placental 11 beta HSD-1 mRNA; but not 11 beta HSD-2 mRNA was increased by E2 treatment. These data do not support a direct effect of exogenous E2 at the level of basal or hypoxemia-stimulated ACTH output, but suggest that elevated E2 concentrations may alter the expression of genes encoding proteins implicated in tonic regulation of fetal HPA function.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMedDate not supplied

Androblastoma: pre-, per- and post-operative steroid hormone and binding protein concentrations in peripheral plasma, cyst fluid and tumor vein.

A case-report of arrhenoblastoma is presented where the endocrine profile has been determined before, during and after removal of the tumor. Sex steroids, cortisol, corticosteroid binding globulin (CBG) and sex steroid binding protein (SBP) were measured in fluid from 2 cysts, tumor vein and peripheral plasma. Hormones were measures by specific RIAs after stepwise chromatography on celite support according to a new elution pattern allowing the resolution of 8 sex steroid in a single chromatographic system. Excessive amounts of androgen, the most prominent being testosterone, and 17-OH-progesterone, but low levels of estrogens and progesterone were found in preoperative plasma. Due to an androgen-directed rise of CBG, large amounts of plasma cortisol were detected. However, preoperative SBP capacity was found to be reduced. The steroid profile of cyst fluids was found to be similar to that of peripheral plasma. Neoplastic cells were found capable of producing an androgen binding protein. These results correlated well with Sertoli-Leydig cell tumors histology, i.e. a testis-like endocrine structure. From the endocrine profile, the steroid biosynthetic pathways are discussed with respect to the possibility that biosynthesis, once the 17-OH-pregnenolone structure was reached, was active along both the delta 5 and delta 4-steroid pathways. The steroid levels in tumor vein and their corresponding gradients to the periphery are discussed with respect to: i) the possibility of metabolic and biosynthetic capacities of cancer cells bearing an undifferentiated steroidogenic appearance, ii) the possibility for tumor steroid secretion by others means than by venous blood and iii) the possibility that both point i) and ii) could be the cause of inconsistent diagnosis significant of endocrine profile as observed in some patients.

Adolescent↗
PubMed2004

Cortisol dynamics following acute severe brain injury.

OBJECTIVE: To study the diurnal rhythm of plasma cortisol and corticosteroid binding-globulin (CBG) in brain-injured patients managed in an intensive care unit (ICU). DESIGN: Observational clinical study. SETTING: Twelve-bed medical/surgical critical care facility. PATIENTS AND PARTICIPANTS: Fifteen acute brain-injured (coma-inducing) patients: nine following trauma and six with subarachnoid haemorrhage (SAH). INTERVENTIONS: One morning and one evening blood sample were obtained from each patient via an existing arterial line at times which coincided with clinically indicated blood tests. MEASUREMENTS AND RESULTS: The total cortisol measurements in this sample of brain-injured patients is similar to the normal reference range. Only two patients had morning total cortisol measurements greater than the reference range, 140-690 nmol/l, and five patients had evening measurements greater than the 80-330 nmol/l reference range. Eight patients demonstrated diurnal variation of plasma cortisol. Plasma CBG was significantly decreased in all 15 brain-injured patients. All patients had a free cortisol percentage greater than the quoted reference of 5% and five patients had measurements between 12-23%. No diurnal variation in CBG was detected. There was no association between age or mode of injury and cortisol secretion. CONCLUSION: Following acute severe brain injury, total serum cortisol is not elevated. This may indicate 'relative' hypocortisolaemia in relation to the clinically assessed stress. However, because of the decline in plasma CBG, plasma free cortisol is increased after acute severe brain injury.

Adolescent↗
PubMed2001

Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma.

OBJECTIVE: To study the time course of corticosteroid binding-globulin (CBG) level and the free cortisol index (FCI) in comparison with total cortisol and ACTH concentrations during acute and prolonged critical illness. DESIGN: Prospective observational clinical study. SETTING: Twenty-bed medical/surgical intensive care unit. PATIENTS AND PARTICIPANTS: Thirty patients with septic shock, eight patients with multitrauma, and forty healthy control subjects. MEASUREMENTS AND RESULTS: During 14 days or until discharge/death, we serially measured serum concentrations of CBG, cortisol, TNF-alpha, IL-6, plasma ACTH immunoreactivity, and the FCI (=cortisol/CBG x 100). We also recorded haemodynamic parameters, APACHE II, ISS, SOFA scores, shock duration, inotrope use, and ICU mortality. In both groups we found markedly decreased CBG levels in the early phase (septic shock: 17.5+/-5.9, and trauma: 16.1+/-2.3 mg/l) in comparison with controls (37.3+/-5.3 mg/l). The FCI was high in this early phase (septic shock: 7.2+/-2.7; trauma: 6.5+/-1.3; controls: 1.25+/-0.76). During follow-up, CBG levels significantly increased, reaching normal levels from day 7 on. The FCI showed an opposite biphasic pattern, with near-normalising FCI values during the second phase. Regression analysis showed a negative correlation between CBG and IL-6 levels (rs=-0.63; P<0.05), but no relation between CBG concentrations and disease severity, shock duration or death was found. CONCLUSIONS: We found extremely low CBG levels in early stage septic shock and multitrauma. These dramatic changes are reflected in a concomitant higher FCI, indicating a higher free cortisol level. A second phase displays increasing and normalising CBG levels, independent from clinical parameters. We believe that CBG plays an active role in the glucocorticoid response to severe stress and in the regulation of cortisol availability to target tissues.

APACHE↗
PubMed1997

Molecular linkage of the human alpha 1-antitrypsin and corticosteroid-binding globulin genes on chromosome 14q32.1.

The genes encoding alpha 1-antitrypsin (alpha 1AT; gene symbol PI) and corticosteroid-binding globulin (CBG) are part of a cluster of structurally related serine protease inhibitor (serpin) genes on human Chromosome (Chr) 14q32.1. This cluster also includes the genes encoding alpha 1-antichymotrypsin (AACT) and protein C inhibitor (PCI), as well as an alpha 1-antitrypsin-related sequence (ATR; gene symbol PIL). In this report we present a detailed restriction map of a 110-kb region of genomic DNA that includes the alpha 1AT, ATR, and CBG genes. Gene order in this interval is tel-alpha 1AT-ATR-CBG-cen, and all three genes are transcribed in a distal-to-proximal orientation. Within the gene cluster, ATR is approximately 12 kb downstream of alpha 1AT, and CBG is about 57 kb downstream of alpha 1AT. Repetitive DNA sequences have been mapped throughout the interval, and several new restriction site polymorphisms in the region are described.

Chromosome Mapping↗
PubMed2003

Homology model of human corticosteroid binding globulin: a study of its steroid binding ability and a plausible mechanism of steroid hormone release at the site of inflammation.

Corticosteroid binding globulin (CBG) and thyroxin binding globulin (TBG) both belong to the same SERPIN superfamily of serine-proteinase inhibitors but in the course of evolution CBG has adapted to its new role as a transport agent of insoluble hormones. CBG binds corticosteroids in plasma, delivering them to sites of inflammation to modify the inflammatory response. CBG is an effective drug carrier for genetic manipulation, and hence there is immense biological interest in the location of the hormone binding site. The crystal structure of human CBG (hCBG) has not been determined, but sequence alignment with other SERPINs suggests that it conforms as a whole to the tertiary structure shared by the superfamily. Human CBG shares 52.15% and 55.50% sequence similarity with alpha1-antitrypsin and alpha1-antichymotrypsin, respectively. Multiple sequence alignment among the three sequences shows 73 conserved regions. The molecular structures of alpha1-antitrypsin and alpha1-antichymotrypsin, the archetype of the SERPIN superfamily, obtained by X-ray diffraction methods are used to develop a homology model of hCBG. Energy minimization was applied to the model to refine the structure further. The homology model of hCBG contains 371 residues (His13 to Val383 ). The secondary structure comprises 11 helices, 15 turns and 11 sheets. The putative corticosteroid binding region is found to exist in a pocket between beta-sheets S4, S10, S11 and alpha helix H10. Both cortisol and aldosterone are docked to the elongated hydrophobic ligand binding pocket with the polar residues at the two extremities. A difference accessible surface area (DASA) study revealed that cortisol binds with the native hCBG more tightly than aldosterone. Cleavage at the Val379-Met380 peptide bond causes a deformation of hCBG (also revealed through a DASA study). This deformation could probably trigger the release of the bound hormone. Figure Stereoscopic view of the ribbon diagram of hCBG complexed with cortisol. The bound cortisol is shown in space filling model in blue. Helices and sheets are shown in red and magenta respectively. Turns are shown in yellow.

Adrenal Cortex Hormones↗
PubMed2005

Modeling of human corticosteroid binding globulin. Use of structure-activity relations in soft steroid binding to refine the structure.

PURPOSE: We propose a model for human corticosteroid binding globulin that is capable of explaining at the molecular level the experimentally observed binding affinities of four ligands. A new method of analyzing data from docking studies is proposed. METHODS: Displacement of radioactive ligand by competitive binding gives the experimentally determined binding affinities of the competitors. A theoretical model, based on homology with crystallographically determined structures, was studied in an automated docking procedure for the determination of theoretical affinities. The docking runs were analyzed by a hybrid principal component-clustering analysis. RESULTS: Of the two binding sites considered, only one--that in the vicinity of Cys 60--can reproduce the experimentally observed order of binding affinities although the lowest energies are found at the site in the vicinity of Cys 228. CONCLUSIONS: Models proposed for proteins should be always conditioned to take into account experimentally observed results. In the current work, we have shown that an informed analysis of theoretical docking studies can lead to a more logical model of the protein, one that can explain and give a deeper understanding of the stereochemical requirements of binding.

Adrenal Cortex Hormones↗
PubMed1978

An in vivo system in man for quantitation of estrogenicity. I. Physiologic changes in binding capacity of serum corticosteroid-binding globulin.

A modified method of measuring the binding capacity of corticosteroid-binding globulin (CBG-BC) in serum using 3H-cortisol saturation-charcoal adsorption is described. Forty serum samples per day can be assayed in duplicate, each sample with a heated nonspecific binding blank (60 degrees C.). The interassay coefficient of variation is less than 6 per cent. All age groups of men and women had similar levels of CBG-BC, except postmenopausal women, whose levels were higher (15.9 +/- 0.2 vs. 18.7 +/- 0.8 microgram per 100 ml., mean +/- standard error of the mean, respectively; z = -3.51, p less than 0.001). The variance of serum levels of CBG-BC throughout the menstrual cycle in five women was small (coefficient of variation = 13 per cent) and showed no relationship to the marked and cyclic changes in estradiol levels (coefficient of variation = 73 per cent). In pregnancy the levels of CBG-BC increased linearly after estradiol levels exceeded 1,300 pg. per milliliter and after estrone levels exceeded 500 pg. per milliliter (r = 0.88, p less than 0.001; and r = 0.85, p less than 0.001, logarithmic regression analysis). The findings of this study indicate that serum levels of CBG-BC are relatively constant in men and menstruating women. In pregnancy after a high threshold of endogenous estrogen is reached, CBG-BC increases in a direct dose-response manner as levels of estradiol increase further.

Adult↗
PubMed1979

Desoxycorticosterone in normal pregnancy. II. Cortisol-dependent fluctuations in free plasma desoxycorticosterone.

Desoxycorticosterone (DOC) secretion increases during pregnancy. Administration of adrenocorticotropic hormone (ACTH) to women during the third trimester of pregnancy was noted previously to result in marked sodium retention, while aldosterone excretion declined. Since urinary tetrahydrodesoxycorticosterone increased substantially, sodium retention resulting from ACTH was ascribed to enhanced DOC secretion. Surprisingly, the elevated plasma DOC in late pregnancy failed to respond consistently to ACTH. Effects of ACTH upon total plasma concentrations and free indexes of DOC and cortisol were studied in pregnant women in the third trimester. As a result of ACTH, plasma cortisol and the free cortisol index increased strikingly; the plasma free DOC index rose markedly in those subjects in whom the total plasma DOC level was not altered appreciably and was unchanged or even increased slightly in the few subjects in whom the total DOC level decreased. The results support the proposition that the plasma free DOC fraction is increased because of displacement from corticosteroid-binding globulin by the ACTH-induced increment in cortisol. Resultant elevations of free DOC would not be evident from customary measurements of the total DOC concentration but, nonetheless, could contribute to sodium retention and also would be available for hepatic metabolism.

Adolescent↗
PubMed1979

Corticosteroid-binding globulin and estrogens in maternal and cord blood.

Corticosteroid-binding globulin (CBG) is produced by the liver in small concentrations and binds steroids with high affinity. Its concentration in the blood is sensitive to endogenous or exogenous estrogens in a dose-response manner and serves as a biological assay for estrogens. CBG concentrations were measured in sera collected from maternal and umbilical vein blood during labor and delivery and at elective cesarean section and correlated with endogenous estradiol and estriol concentrations. CBG and estradiol concentrations of maternal blood were significantly exceeded those of maternal serum. A highly significant increase in cord blood estriol concentration was found following vaginal delivery compared to elective cesarean section, indicating an increase in adrenal activity due to the stress of labor. CBG levels correlated directly with maternal estradiol but not estriol cencentrations. Cord blood CBG concentration varied little despite a wide range of estrogen concentrations. The physiologic significance of CBG concentrations in maternal and fetal blood is discussed.

Cesarean Section↗
PubMed1980

Comparison of metabolic and clinical effects of four oral contraceptive formulations and a contraceptive vaginal ring.

A group of 100 women desiring OC received one of the following four formulations on a randomized basis: (1) mestranol 50 micrograms and norethindrone 1 mg, , (2) ethinyl estradiol 50 micrograms and norethindrone 1 mg, (3) ethinyl estradiol 35 micrograms and norethindrone 1 mg, and (4) ethinyl estradiol 30 micrograms and levonorgestrel 150 mg. An additional 10 women received a CVR containing levonorgestrel and estradiol. Measurement of a large number of serum chemistries, lipids, proteins, clotting factors, and liver enzymes was obtained before and 3 and 6 months after starting medication. Clinical factors such as weight, blood pressure, bleeding or spotting, or any adverse side effects were also recorded. There was no significant difference in the metabolic parameters measured among the four oral contraceptives except the increase in angiotensinogen was slightly less in the groups receiving the compounds with 30 or 35 micrograms estrogen and the groups receiving the norgestrel compound had no increase in triglycerides and a slight decrease in cholesterol levels. When the CVR was compared with all oral contraceptives it was found to produce no change in angiotensinogen levels and a decrease in triglycerides. Some of each group of OC users had a lowering of antithrombin III to abnormal levels but none of the CVR users had his amount of decrease. As oral steroids with 30 or 35 micrograms of estrogen do not produce significantly less metabolic alteration than do compounds with 50 micrograms of estrogen, it is unlikely that their use will reduce the incidence of the uncommon serious adverse effects associated with OC use. However, since the CVR's did not increase angiotensinogen, their use as contraceptives will most likely not produce hypertension and possibly the other serious circulatory problems which are increased in some OC users.

Adolescent↗
PubMed1981

Corticosteroid-binding globulin as a biologic assay for endogenous estrogen in patients with and without endometrial carcinoma.

Serum corticosteroid-binding globulin (CBG) concentrations in blood respond to endogenous or exogenous estrogens in a dose-response manner and serve as a biologic assay for estrogens. Because endometrial carcinoma is associated with unopposed or excessive estrogen stimulation, the CBG binding capacity of sera of patients with endometrial cancer was compared to that of normal premenopausal and postmenopausal women. The mean +/- SEM values for CBG concentrations in patients with endometrial cancer (28.3 +/- 1.3 mg/L) were significantly greater than CBG concentrations in premenopausal women (21.4 +/- 0.9 mg/L, p less than 0.001), but not significantly different from those of normal postmenopausal women (26.7 +/- 1.2 mg/L). Patients with polycystic ovarian disease, a risk factor for endometrial carcinoma, also had CBG concentrations significantly greater than those of normal premenopausal women (27.9 +/- 1.8 mg/L, p less than 0.01). CBG levels decline with age (r = -0.6474, p less than 0.05) but are unaffected by body weight or percent ideal body weight. These results indicate that CBG can distinguish categories of patients at risk for endometrial carcinoma, but it is not an effective biochemical marker for patients in these high-risk groups who have or will develop endometrial carcinoma.

Adult↗